For many years, surgical tissue closure has been accomplished by a variety of fundamental techniques such as the use of clamps, staples, or a variety of sutures. Disadvantages associated with use of those techniques in certain situations has led to the development of new techniques for joining damaged mammalian tissues and reducing or preventing the loss of blood or other bodily fluids as well.
One approach has been the development of tissue adhesives for joining tissues, derived from either natural or synthetic products. Adhesive bonding with natural products such as fibrin or glues derived from mollusks such as mussels and barnacles has shown promise. Fibrin glue has been prepared by reacting a cryoprecipitate of fibrinogen and thrombin in the presence of a calcium ion to produce fibrin monomer. This monomer reacts in the presence of a factor found in the patient's blood (Factor XIII) to form a polymer. These fibrin glues have found use in topical and spray applications as a hemostatic agent on bleeding anastomoses, bleed points caused by needle holes or suture lines, and on the heart surface to control bleeding. The fibrin glues have only a modest tensile strength and therefore have not found significant use for repairing tissues which are subjected to moderate or high stresses, and particularly cyclic ones.
Barnacle glue has shown promise since its polymerization is rapid and occurs under conditions which are similar to the environment in which they would be used. It also maintains its adhesive properties under adverse chemical conditions. However, under typical use conditions, the resulting adhesive joint has unacceptable tensile strength. Preparation of glues from mollusks is difficult, however, and large quantities of material must be processed to obtain a significant amount of adhesive. To prepare 1 milligram of adhesive from barnacles requires the harvest and treatment of at least 150 barnacles.
For these reasons, a great deal of attention has been given to the development of synthetic adhesive systems. Especially prominent has been the development of adhesive and hemostasis-inducing compositions comprising fast curing monomers such as dialkyl methylene malonates (U.S. Pat. No. 3,221,745) and monomeric lower alkyl 2-cyanoacrylates (U.S. Pat. Nos. 3,223,083 and 3,264,249). Because the lower alkyl 2-cyanoacrylates did not appear to combine the desired, if not the necessary, properties of low toxicity and adequate adsorption by tissues, the use of alkoxyalkyl 2-cyanoacrylate was developed (U.S. Pat. No. 3,559,652). Other polymers presently under investigation as tissue adhesives include polyurethanes and epoxy resins. The latter two polymer systems suffer disadvantages of having limited "pot life" or "open time," exhibiting significant exothermic reaction when polymerized (or cured) and being toxic to surrounding tissues.
It is advantageous for tissue adhesives to capable of being absorbed or degraded in the body, otherwise described as bioabsorbable or biodegradable. Secondly, it is obviously desirable that a device used in vivo should only remain as long as necessary to insure proper healing. This should reduce or prevent adverse tissue reactions and foreign body responses. In orthopedic applications, absorbable pins and plates that could perform in place of metal implants would require only a single surgical procedure. Absorbable polymers would also be useful for use with implantable systems for long-term drug delivery.
Shalaby in Encyclopedia of Pharmaceutical Technology, Swarbrick and Boylan, Eds., Marcel Dekker, Inc., New York, 1988, pp. 465-476, has classified bioabsorbable polymers into three groups: soluble, solubilizable, and depolymerizable. Soluble polymers are water-soluble and have hydrogen-bonding polar groups, the solubility being determined by the type and frequency of the polar group(s). Solubilizable polymers are usually insoluble salts such as calcium or magnesium salts of carboxylic or sulfonic acid-functional materials which can dissolve by cation exchange with monovalent metal salts. Depolymerizable systems have chains that dissociate to simple organic compounds in vivo under the influence of enzymes or chemical catalysis.
The response of tissues to biodegradable materials is dependent on the rate of absorption, but more importantly, it is regulated by the toxicity of the degradation products. Thus, it is important to have controlled absorption to decrease the toxicity and reaction of surrounding tissue to products that do elicit a response. It also is important to ensure that the mechanical properties of the polymer are maintained for sufficient time to allow proper healing. Thus, absorbable polymeric adhesives and the products of their bioabsorption must be compatible with the surrounding tissues.
2-Cyanoacrylates bond rapidly to tissues and form strong adhesive joints. Their properties may be modulated by varying their substituent groups. They are well-suited for biological applications since, unlike other adhesives such as epoxy resins and polyurethanes, 2-cyanoacrylates may be used as pure monofunctional monomers having well-defined properties. They homopolymerize rapidly at room temperature in the presence of weakly basic moieties such as water and other weakly basic species present in body fluids. Since their introduction in 1958, they have found use in many surgical applications such as hemostasis, as sealants for retrofilling, and as general tissue adhesives. A 2-cyanoacrylate suitable for use as a tissue adhesive should be non-toxic and biodegradable, should wet and spread on tissue substrates, and polymerize quickly to a thin, polymeric film. The polymeric adhesive should have a degree of flexibility, especially when bonding soft tissues. Biodegradability is especially important because the adhesive should be replaced by natural tissues and not slow or bar complete healing.
In the homologous series of poly(alkyl 2-cyanoacrylates) the lower homologs such as the methyl ester exhibit the highest rate of bioabsorption but also elicit the greatest tissue response. They also do not wet, spread or polymerize on biological substrates as rapidly as the higher homologs. On the other hand, the higher alkyl esters, such as the isobutyl, n-butyl or octyl ester, elicit relatively less tissue reaction but degrade too slowly, if at all. Therefore, the main drawbacks for use of the alkyl 2-cyanoacrylates has been their lack of practical biodegradability. Accordingly, Linden and Shalaby [U.S. Pat. No. 5,350,798 (1994)] developed an absorbable tissue adhesive formulation that is based on 2-cyanoacrylate and biocompatible oxalate polymers as reactive plasticizers and thickening agents to allow modulus matching of the adhesive and substrate. More specifically, the Linden/Shalaby system comprises at least one 2-cyanoacrylate ester of the general formula (I). ##STR1##
wherein R is selected from the group consisting of alkyl groups having from 1 to about 8 carbon atoms and, preferably, alkoxyalkyl groups having the formula R.sub.1 --O--R.sub.2 --wherein R.sub.1 is an alkyl group having from 1 to about 8, preferably 2 to 3 carbon atoms and R.sub.2 is an alkylene group having from 3 to about 6, preferably 3 to 4 carbon at 5, in an admixture with from about 2 percent to about 25 percent, preferably about 5 to 10 percent, of at least one oxalic acid polymer of the general formula (II) ##STR2##
wherein each R.sub.3 is an alkylene group having from 2 to about 4 carbon atoms, each p is an integer from 1 to about 4, with the proviso that not more than about 1 of each 20 p's is 1, and n is the degree of polymerization which results in a polymer which does not initiate polymerization upon mixing with the 2-cyanoacrylate monomer and standing for about 12 hours. Suitable alkylene groups include but are not limited to ethylene, propylene, trimethylene, butylene, isobutylene, and tetramethylene. It is preferred that p have a value of 3 and R.sub.3 is ethylene. Where p is 1 it is preferred that R.sub.3 is trimethylene.
However, the Linden/Shalaby systems are limited to compliant absorbable oxalate-based copolyesters having short polyalkylene oxide segments (p=1-4) which limit the broad utilization of the cyanoacrylate as tissue adhesives for adjoining or sealing tissues where the adhesive is required to have a modulated absorption profile or absorbs over a longer period of time ranging between 0.25 to 3 years, depending on the subject tissue, its location in the human body, its mechanical properties, and the functional requirements associated with the adhesive-repaired site. Recognizing the outstanding properties of cyanoacrylates as tissue adhesive, sealants, and blocking agents, and the existing need to repair different biological tissues having a broad range of mechanical properties and healing profiles, evoked the need to develop new cyanoacrylate formulations to meet such requirements. The present invention provides novel 2-cyanoacrylate formulations with the sought properties.